Human recreational use of the hemp plant Cannabis sativa (“marijuana”) and anecdotal attempts to exploit it for potential therapeutic benefit have been documented throughout millennia. Some of marijuana's popularity as a recreational substance and medicament reflects its ability to alter sensory perception and relieve anxiety. Other medicinal effects of marijuana unrelated to its psychoactive properties, such as pain relief, have also been recorded in ancient texts. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol are the two major phytocannabinoids that were identified along with approximately 60 other phytocannabinoids present in Cannabis. Δ9-THC, cannabidiol, and some other phytocannabinoids are bioactive with, for example, intriguing anti-inflammatory, anticonvulsive, and anti-emetic effects of potential therapeutic value. However, Δ9-THC is regarded as the sole psychotropic cannabinoid in Cannabis. Given Δ9-THC's psychotropic effects, many biological investigations employed brain and brain plasma membranes as study-objects. Consensus data describing several key characteristics of cannabinoid action emerged: Δ9-THC, its synthetic analogs and related compounds elicit biological effects in a stereo- and structurally selective manner; their binding to brain plasma membranes is avid, saturable, stereospecific, concordant with in vitro and in vivo bioresponses (e.g., adenylyl cyclase inhibition, analgesia), and nonrandom in select brain regions.
These characteristics strongly implied that cannabinoid pharmacology is receptor-mediated, spurring the search for discrete mammalian cannabinoid receptors whose activation by Δ9-THC would elicit psychotropic effects. The search led to the discovery and cloning of two G protein-coupled receptors (GPCRs) for cannabinoids (CB), designated CB1 and CB2, which in humans share≈44% sequence homology. The CB1 receptor subtype is localized primarily in the central nervous system (CNS), reflecting its prevalence as the most abundant GPCR in brain. CB1 receptors are distributed among the cortex, cerebellum, hippocampus, and basal ganglia, brain regions that control motor, cognitive, emotional, and sensory functions. Hence, central CB1 receptor activation mediates most cannabinoid psychotropic and behavioral effects. The CB1 receptor is also present in high density in the brainstem, hypothalamus, and pituitary gland, loci influencing pain perception; hormonal activity; thermoregulation; and cardiovascular, gastrointestinal, and respiratory physiology. CB1 receptors at peripheral sites (e.g., adipocytes, liver, uterus) help regulate such basic physiological processes as energy balance and reproduction. Although detectable at exceedingly low levels in brain, CB2 receptors are expressed mainly by immune and hematopoietic cells, osteoclasts, and osteoblasts and mediate immune responses, inflammation, inflammatory and neuropathic pain, and bone remodeling. Largely because of this psychoactivity as well as its prevalence and early availability in synthetic form as a research tool, Δ9-THC attained the status of prototypic cannabinoid and became the focus of many pharmacological and mechanistic studies.
Much of this research in vivo was aimed at elucidating the effects of Δ9-THC in experimental animals as well as human subjects with the aid of newly-synthesized Δ9-THC analogs and related compounds such as nabilone, Δ8-tetrahydrocannabinol, 11-OH-Δ9-tetrahydrocannabinol, cannabidiol (ex., GWP42003), cannabinol, Δ9-tetrahydrocannabivarin (ex., GWP42004), CP-47,497, dexanabinol, Ajulemic acid, HU-210, 8-β-OH-tetrahydrocannabinol, 8-α-OH-tetrahydrocannabinol, SAB-378, nabitan, menabitan, A-40174, Org 28611, nonabine, BAY38-7271, GRC10693, S-777469, AZD1940, GW-842,166X, GW-405,833, levonantradol, dimethylheptylpyran and the AM1703 analog PRS-211,375 (Cannabinor). Some of these compounds were radiolabeled and used as molecular probes as well. Virtually all cannabinoid-related medications granted regulatory approvals thus far are directly related to Cannabis, most of which act as agonists at the CB1 and CB2 receptors.
It has been suggested that tetrahydrocannabivarin acts as a CB1 neutral antagonist while Δ9-THC is known to act as a CB1 partial agonist. Δ9-THC (dronabinol, Marinol®) and its synthetic analog, the CB1/CB2 agonist, nabilone (Cesame®) are licensed as anti-nausea and anti-emetic medications for chemotherapy patients. Nabilone is also approved as an appetite stimulant to treat acquired immune deficiency syndrome-related cachexia. Sativex®, a standardized Cannabis extract containing an approximately equal mixture of the two phytocannabinoids (Δ9-THC and cannabidiol) formulated as a sublingual spray, was first licensed for alleviation of neuropathic pain in multiple sclerosis patients and subsequently approved for cancer pain relief. The low reported frequency of abuse and neurocongnitive side-effects of Cannabis extracts/Δ9-THC derivatives has invited their continued clinical evaluation. Aside from nabilone, other synthetic cannabinoid-receptor activators such as CP55,940 have been studied clinically for alleviation of emesis; motor-related symptoms in patients with multiple sclerosis, Tourette's syndrome, or Parkinson's disease; intraocular pressure in glaucoma patients; neuropathic pain; or post-trauma brain damage.